Co-evolution of host and pathogen: HIV as a...
Transcript of Co-evolution of host and pathogen: HIV as a...
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Co-evolution of host and pathogen: HIV as a model
Can Keşmir
Theoretical Biology/Bioinformatics Utrecht University, NL [email protected]
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Outline
● Does HIV adapt to monomorphic human molecules?
● Polymorphic molecules: What is the mechanism behind different disease outcomes?
● Can we learn more about which molecules/mechanisms are important in disease induction by studying evolution of SIV in African monkeys?
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Antigen processing and presentation (Class I MHC)
© E. Reits, NKI
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How can a pathogen “hide” from CTL response?
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Specificity of molecules
NetMHC
NetChop-20S
NetChop-Cterm
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Specificity of the molecules
● Proteasome ● TAP ● MHC ● TCR
Are monomorphic molecules easy targets of escape during HIV infection?
30%
70%
1-5%
0.001%
monomorphic
monomorphic
polymorphic
highly diverse
Boris Schmid (UU)
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Adaptation on single host level● Two full HIV genome
sequencies (1986 and 1997) of a long term survivor
● Total of 66 non-silent mutations
● 62 mutations can be associated with CTL responses given the patient MHCs
Escape from strong epitopes: 13
MHC escapes: 10
Processing escapes: 7
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Adaptation on population level
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Why HIV is not evading processing?
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Shadowing due to MHC polymorphism
X
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Conclusions: adaptation to monomorphic molecules?
● At the population level processing escape mutants do not get fixed because of the shadowing by MHC polymorphism
● The degeneracy of proteasome and TAP might make make it difficult for HIV to evade antigen processing (we need to analyse more data to be able to say this).
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MHC effect on AIDS: Low Risc
Carrigton, et al. 2003
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MHC effect on AIDS: High Risc
Gao, et al. 2001
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What is special about Low risc MHC molecules?
● Rare allele advantage????
● Are they differing in their presentation
profile? (Targetting different proteins?)
Jose' Borghans & Rob de Boer (UU)
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HIV epitopes in LANL database
B53 is also a high risc allele, but there are not yet enough epitopes known!
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Genome-wide predictions
● Predict MHC binding for Low RH and High RH alleles for all 9mers/10mers
● Rank for each allele all 9mers/10mers of HIV according to their MHC binding
● For each HIV protein look at the rank of the best 3 “epitopes”
● Is there a significant difference in the rank of 3 best epitopes between low and high RH alleles?
● Remember: larger proteins have more chance of having high ranking 9mers!
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Genome wide predictions
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Why targetting p24 is protective?
●p24 is the capsid protein●Expressed in large numbers (>1000 copies per virion)●Expressed very early during infection●Crucial for the production of new virions --> highly conserved
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However.....
● Even elite suppressors of HIV can have mutations in p24 (Barley et al J. Exp. Med. 2006)
● These mutations come with a high fitness cost: replication capacity is 10-fold lower
HIV escapes the host immune response, but heavily crippled
● The viral load remains very low --> no progression to AIDS
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Low Risc MHC target constrained regions of p24
Anne Mølgaard, CBS
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Conclusions: MHC effect on adaptation of HIV
● Immune selection pressure can cause escape mutants with high fitness cost.
● “Protective” MHC molecules are those that target constrained regions of HIV
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Primates and SIV/HIV
Gordon, et al 2005
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Natural host response to SIVsmby S. mangabeys
● Prevelance upto 60% or more, increasing with age
● Normal CD4 T cell counts, no signs of hyper-activation
● High viral loads, however hardly any AIDS● SIVsm is not ignored by the host, but a mild T
cell response is generated
Rhesus macagues infected with modified SIVsm develop AIDS
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Chimpanzee and SIV● Up to 60% infected with SIVcpz ---> no AIDS● 200 chimpanzees so far infected experimentally with HIV-
1 --> only 1 case of possible AIDS.● Low viral loads --> Efficient T cell response???● MHC diversity is much lower compared to human.
Especially protective MHC-B has lower diversity.Has been through a severe selection (bottleneck)
● Common MHC molecules in the chimpanzee population target the same epitopes as human long-term non-progressors
Can we find more signs of adaptation/selection?
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Comparative genomics
AIDSAIDS AIDS
SIVmac SIVcpz HIV-1/2
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Comparative analysis● Lineage specific genes (~500) difficult to predict the
function
● Look for orthologs in macaques and human that are not existing chimpanzee
● PanTro2.1 (March 2006) & Ensemble automatic orthology detection (manual check afterwards)
● There are 312 ortholog groups that are deleted in chimpanzee
● 153 of these have GO annotations
● 12 genes are related to immune response and thus our candidates for possible host adaptation
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Almost for sure missing in chimpanzee
●ICEBERG: inhibitor of caspase-1. ●IL1F7 & ILF18: members of IL1 super family
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Some genes are very diverged!
Chimp Consortium, Nature, 2005
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CCR5Human MNYQTSTPYYDIDYGTSEPCQKVNVRQIAARLLPPLYSLVFIFGFVGNVLVVLILIDCKKChimp MDYQVSSPIYDIDYYTSEPCQKINVKQIAARLLPPLYSLVFIFGFVGNMLVILILINCKR *:**.*:* ***** *******:**:**********************:**:****:**: Human LKSMTDIYLLNLAISDLLFLLTIPFWAHYAADQWTFGNKMCQLLTGLYYIGFFTGNFFIIChimp LKSMTDIYLLNLAISDLFFLLTVPFWAHYAAAQWDFGNTMCQLLTGLYFIGFFSGIFFII *****************:****:******** ** ***.*********:****:* **** Human LLTMDRYLAIVHAVSASKARTVTFGVVTSGIAWVVAVLASFPRIIFTRSQKEGSRFTCSPChimp LLTIDRYLAIVHAVFALKARTVTFGVVTSVITWVVAVFASLPGIIFTRSQKEGLHYTCSS ***:********** * ************ *:*****:**:* ********** ::***. Human HFPPSQHHFWKNFQALKMSVLGLILPLLVMIIGYSAILKTLLRCRNEKKRHKAERLIFVIChimp HFPYSQYQFWKNFQTLKIVILGLVLPLLVMVICYSGILKTLLRCRNEKKRHRAVRLIFTI *** **::******:**: :***:******:* **.***************:* ****.* Human MIVYFLFWAPYNIVLLLSTFQEFFGLNNCNSSNRLDQAMQITETLGMTHCCINPIIYAFVChimp MIVYFLFWAPYNIVLLLNTFQEFFGLNNCSSSNRLDQAMQVTETLGMTHCCINPIIYAFV *****************.***********.**********:******************* Human GEKFRRYLSLFFRKHIARRFCKCCPIFQGELPDRVSSVYTRSTGEQEISVALChimp GEKFRNYLLVFFQKHIAKRFCKCCSIFQQEAPERASSVYTRSTGEQEISVGL *****.** :**:****:******.*** * *:*.***************.*
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Conclusions
● Processing do not shape HIV evolution, because:
1. MHC polymorphism shadow the immune selection pressure on processing
2. The processing is degenerate and thus difficult to escape from
● MHC alleles targeting constrained regions of HIV are protective.
● Chimpanzee do not develop AIDS, because they lack some immuno-regulatory genes or HIV/SIV receptors?
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Immuno-epidemiology
What immune response is controlling HIV?
● CD8 T cells: MHC polymorphism
● APOBEC3G: 8 SNPs in 384 AA
● Toll like receptors: Many SNPs in each gene!
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Acknowledgements
TBB, Utrecht● Boris Schmid● Jose' Borghans● Rob J. de Boer
CBS, DTU, Denmark● Anne Mølgaard● Ole Lund● Morten Nielsen● Claus Lundegaard● ………